The invention is directed to method of inducing opioid analgesia and anesthesia in mammals, including humans, without suppressing respiration.
Opiates have long been known to disrupt respiratory rhythm and to depress breathing and respiratory sensitivity to CO2 (Jaffe and Martin, 1990). The pons and medulla are known to be the primary sites where opiate drugs produce these respiratory effects (Id.). Endogenous opioids as well as xcexc- and xcex4-subtypes of opioid receptors are present in essentially all respiratory regions of the pons and medulla (Yeadon and Kitchen, 1989). In vivo and in vitro investigations have shown that exogenous opioids depress inspiratory and expiratory neuronal activity postsynaptically (Denavit-Saubie"", Champagnat and Zieglgansberger, 1978), as well as presynaptically (Johnson, Smith and Feldman, 1996). The underlying cellular mechanisms responsible for the opiate effects on respiration have not, however, been elucidated.
Opiates are widely used medicinal agents. However, because they depress breathing, their use is contraindicated in many instances, especially in patients with compromised cardiovasculare and pulmonary function. Thus, there has been a long-felt need to harness the analgesic power of the opiates, without depressing the respiratory function of the patient.
In the present invention, actions of opiates were analyzed on bulbospinal inspiratory and expiratory neurons and on non-bulbospinal postinspiratory neurons of the medulla in cats that were either anesthetized with pentobarbital or xcex1-chloralose, or rendered comatose in the unanesthetized state by midcollicular decerebration. The cat respiratory network is similar to that of man. The different cat preparations were used to determine how opiate-induced respiratory responses are affected by anesthetics with different effects on the reticular activating system (RAS; Killlam, 1967). The RAS provides a source of excitatory synaptic input to the brainstem respiratory network (Richter, Ballantyne and Remmers 1986), and is also a site of action for opiates (Killam, E. K. 1963). Most of the respiratory neurons in this study were identified as bulbospinal and therefore might be directly responsible for opiate-mediated depression of tidal volume (Jaffe and Martin, 1990; Shook et al., 1990) and decreased chest wall compliance (Marty and Desmonts, 1981; Bennett, Abrams, Van Riper and Horrow, 1997; Neidhart, Burgener and Suter, 1989).
With respect to this invention, it was also important to ascertain whether anesthesia would compromise the potential of D1 dopamine agonists to antagonize opioid-mediated respiratory depression. This is an important issue because opioids and anesthetics are frequently used in combination during surgical procedures.
Another objective of this work was to determine if opioid depression of the respiratory network is reversed by administration of selective D1-dopamine receptor agonists. Reversal of opioid depression with a D1 agonist had been previously demonstrated by Lalley and coworkers in an in vitro brainstem-spinal cord preparation of the neonatal rat (Ballanyi, Lalley, Hoch and Richter 1997). This work, however, cannot be extrapolated to in vivo efficacy due to the rudimentary nature of the in vitro spinal cord preparation. Experimentation in a more developmentally mature and intact animal model was required to determine if this type of antagonism is also possible in vivo in the respiratory network of mature mammals. The results discussed herein reveal that D1 agonists are indeed effective in each of the different cat animal models, and reinstate a normal respiratory rhythm without directly stimulating the network or increasing brain stem or carotid body chemoreceptor sensitivity.
Thus, a first embodiment of the present invention is directed to a pharmaceutical composition for inducing analgesia or anasthesia in a mammalian subject, while simultaneously eliminating or inhibiting respiratory depression in the subject. The pharmaceutical composition comprises, in combination, an opiate or opioid analgesic or anesthetic, a D1-dopamine receptor agonist, and a pharmaceutically-suitable carrier therefor. More specifically, in the preferred composition, the opiate or opioid is selected from the group consisting of alfentanil, buprenorphine, carfentanil, codeine, dihydrocodeine, diprenorphine, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, LAAM, levorphanol, meperidine, methadone, morphine, naloxone, naltrexone, beta-hydroxy-3-methylfentanyl, oxycodone, oxymorphone, propoxyphene, remifentanil, sufentanil, tilidine, tramadol, enriched or pure enantiomers or diastereomers thereof; racemic mixtures thereof; and pharmaceutically-suitable salts thereof; and the D1-dopamine receptor agonist is selected from the group consisting of (xc2x1)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol; (xe2x88x92)-(6aR,12bR)-4,6,6a,7,8,12b-hexahydro-7-methylindolo{4,3-a}phenanthridine; (xc2x1)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo-{a}phenanthridine; (xc2x1)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (xc2x1)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; ABT 431; enriched or pure enantiomers or diastereomers thereof; racemic mixtures thereof; and pharmaceutically-suitable salts thereof.
A second embodiment of the invention is directed to a method of inhibiting respiratory depression in mammals during treatment with opiates or opioids. The method comprises administering to a mammalian subject being treated with opiates or opioids, an amount of a D1-dopamine receptor agonist, the amount being sufficient to inhibit respiratory depression. The preferred D1-dopamine receptor agonists for use in the method are the same as those listed in the previous paragraph. Likewise, the method will function with equal success regardless of the specific opiate or opioid that is being used to treat the subject.